Implantable device for sustained release of a macromolecular drug compound

ABSTRACT

An implantable device for delivery of a macromolecular drug compound is provided. The device comprises a core having an outer surface and a membrane layer positioned adjacent to the outer surface of the core. The core comprises a core polymer matrix within which is dispersed a drug compound having a molecular weight of about 0.5 kDa or more, the polymer matrix containing a hydrophobic polymer. Further, the membrane layer comprises a membrane polymer matrix within which the macromolecular drug compound is optionally dispersed. The membrane polymer matrix contains a hydrophobic polymer in combination with a hydrophilic compound, and the weight ratio of the hydrophobic polymer to the hydrophilic compound within the membrane polymer matrix ranges from about 0.25 to about 200.

RELATED APPLICATIONS

The present application claims priority to U.S. Application Ser. No.62/675,994 (filed on May 24, 2018), which is incorporated herein in itsentirety by reference thereto.

BACKGROUND OF THE INVENTION

Biologic macromolecule drug compounds are typically composed of one ormore oligomeric or polymeric chains, forming a three-dimensionalstructure held together by non-covalent forces. While these drugcompounds have the potential for a multitude of therapeutic benefits, ithas been traditionally difficult to controllably deliver these compoundsover a sustained period of time. Many implantable delivery devices, forexample, are formed by solubilizing a drug compound into a matrixpolymer. These solubilized drug molecules can diffuse through theimplant and be released into a patient. Unfortunately, however, drugelution is highly dependent upon the diffusion coefficient of the drugmolecule, which in turn, is inversely proportional to the molecularweight of the drug molecule. Thus, macromolecular drug compounds tend tohave a lower diffusion coefficient due to their larger molecular weight.Further, such compounds often have chain length entanglements, which caneven further reduce the effective diffusion coefficient. In light ofthese difficulties, a need continues to exist for an implantabledelivery device that is capable of delivering a macromolecular compoundin effective amounts over a sustained period of time.

SUMMARY OF THE INVENTION

In accordance with one embodiment of the present invention, animplantable device for delivery of a macromolecular drug compound isdisclosed. The device comprises a core having an outer surface and amembrane layer positioned adjacent to the outer surface of the core. Thecore comprises a core polymer matrix within which is dispersed a drugcompound having a molecular weight of about 0.5 kDa or more, the polymermatrix containing a hydrophobic polymer. Further, the membrane layercomprises a membrane polymer matrix within which the macromolecular drugcompound is optionally dispersed, wherein the membrane polymer matrixcontains a hydrophobic polymer in combination with a hydrophiliccompound. The weight ratio of the hydrophobic polymer to the hydrophiliccompound within the membrane polymer matrix ranges from about 0.25 toabout 200.

Other features and aspects of the present invention are set forth ingreater detail below.

BRIEF DESCRIPTION OF THE DRAWINGS

A full and enabling disclosure of the present invention, including thebest mode thereof, directed to one of ordinary skill in the art, is setforth more particularly in the remainder of the specification, whichmakes reference to the appended drawings in which:

FIG. 1 is a perspective view of one embodiment of the implantable deviceof the present invention;

FIG. 2 is a cross-sectional view of the implantable device of FIG. 1 ;

FIG. 3 is a perspective view of another embodiment of the implantabledevice of the present invention;

FIG. 4 is a cross-sectional view of the implantable device of FIG. 3 ;

FIG. 5 is a graph showing the cumulative release ratio of bromelainversus release time (hours) for Examples 1-4;

FIG. 6 is a graph showing the release rate of bromelain (μg/h) versusrelease time (hours) for Examples 1-4;

FIG. 7 is a graph showing the cumulative release ratio of bromelainversus release time (hours) for Examples 5-7;

FIG. 8 is a graph showing the release rate of bromelain (μg/h) versusrelease time (hours) for Examples 5-7;

FIG. 9 is a graph showing the cumulative release ratio of bromelainversus release time (hours) for Examples 8-13;

FIG. 10 is a graph showing the release rate of bromelain (μg/h) versusrelease time (hours) for Examples 8-13;

FIG. 11 is a graph showing the cumulative release ratio of bromelainversus release time (hours) for Examples 14-18;

FIG. 12 is a graph showing the release rate of bromelain (μg/h) versusrelease time (hours) for Examples 14-18;

FIG. 13 is a graph showing the cumulative release ratio of bromelainversus release time (hours) for Examples 19-20;

FIG. 14 is a graph showing the release rate of bromelain (μg/h) versusrelease time (hours) for Examples 19-20;

FIG. 15 is a graph showing the cumulative release ratio of bromelainversus release time (hours) for Examples 21-23;

FIG. 16 is a graph showing the release rate of bromelain (μg/h) versusrelease time (hours) for Examples 21-23;

FIG. 17 is a graph showing the cumulative release ratio of collagenversus release time (hours) for Examples 24-27;

FIG. 18 is a graph showing the release rate of collagen (μg/h) versusrelease time (hours) for Examples 24-27;

FIG. 19 is a graph showing the cumulative release ratio of bromelainversus release time (hours) for Examples 28-30; and

FIG. 20 is a graph showing the release rate of bromelain (μg/h) versusrelease time (hours) for Examples 28-30.

Repeat use of references characters in the present specification anddrawing is intended to represent same or analogous features or elementsof the invention.

DETAILED DESCRIPTION

It is to be understood by one of ordinary skill in the art that thepresent discussion is a description of exemplary embodiments only, andis not intended as limiting the broader aspects of the presentinvention.

Generally speaking, the present invention is directed to an implantabledevice that is capable of delivering a macromolecular drug compound forprohibiting and/or treating a condition, disease, and/or cosmetic statein a patient (e.g., human, pet, farm animal, race horse, etc.). Theimplantable device may have a variety of different geometric shapes,such as cylindrical (rod), disc, ring, doughnut, helical, elliptical,triangular, ovular, etc. In one embodiment, for example, the device mayhave a generally circular cross-sectional shape so that the overallstructure is in the form of a cylinder (rod) or disc. In suchembodiments, the device will typically have a diameter of from about 0.5to about 50 millimeters, in some embodiments from about 1 to about 40millimeters, and in some embodiments, from about 5 to about 30millimeters. The length of the device may vary, but is typically in therange of from about 1 to about 25 millimeters. Cylindrical devices may,for instance, have a length of from about 5 to about 50 millimeters,while disc-shaped devices may have a length of from about 0.5 to about 5millimeters.

Regardless of the particular shape or size, the device is multilayeredin that it contains at least one membrane layer positioned adjacent toan outer surface of a core. The core contains a core polymer matrix thatincludes a hydrophobic polymer and a macromolecular drug compound thatis dispersed within the core polymer matrix. Typically, macromoleculardrug compounds will constitute from about 5 wt. % to about 60 wt. %, insome embodiments from about 10 wt. % to about 50 wt. %, and in someembodiments, from about 15 wt. % to about 45 wt. % of the core, whilethe core polymer matrix constitutes from about 40 wt. % to about 95 wt.%, in some embodiments from about 50 wt. % to about 90 wt. %, and insome embodiments, from about 55 wt. % to about 85 wt. % of the core. Themembrane layer(s) also contain a membrane polymer matrix within which adrug compound may optionally be dispersed. The membrane polymer matrixcontains a combination of a hydrophobic polymer and a hydrophiliccompound (e.g., hydrophilic polymer) that is soluble and/or swellable inwater. To help achieve the desired release of the macromolecular drugcompound, the weight ratio of the hydrophobic polymers to thehydrophilic compounds within the membrane polymer matrix is selectivelycontrolled, such as within a range of from about 0.25 to about 200, insome embodiments from about 0.4 to about 80, in some embodiments fromabout 0.8 to about 20, in some embodiments from about 1 to about 16, andin some embodiments, from about 1.2 to about 10.

Through selective control over the particular nature of the core andmembrane layer(s) as noted above, and the manner in which they areformed, the present inventors have discovered that the resulting devicecan be effective for sustained release over a macromolecular drugcompound over a prolonged period of time. For example, the implantabledevice can release the drug compound for a time period of about 5 daysor more, in some embodiments about 10 days or more, in some embodimentsfrom about 20 days to about 60 days, and in some embodiments, from about25 days to about 50 days (e.g., about 30 days). Further, the presentinventors have also discovered that the drug compound can be released ina controlled manner (e.g., zero order or near zero order) over thecourse of the release time period. After a time period of 15 days, forexample, the cumulative release ratio of the implantable device may befrom about 20% to about 70%, in some embodiments from about 30% to about65%, and in some embodiments, from about 40% to about 60%. Likewise,after a time period of 30 days, the cumulative release ratio of theimplantable device may still be from about 40% to about 85%, in someembodiments from about 50% to about 80%, and in some embodiments, fromabout 60% to about 80%. The “cumulative release ratio” may be determinedby dividing the amount of the drug compound released at a particulatetime interval by the total amount of drug compound initially present,and then multiplying this number by 100.

Of course, the actual dosage level of the drug compound delivered willvary depending on the particular drug compound employed and the timeperiod for which it is intend to be released. The dosage level isgenerally high enough to provide a therapeutically effective amount ofthe drug compound to render a desired therapeutic outcome, i.e., a levelor amount effective to reduce or alleviate symptoms of the condition forwhich it is administered. The exact amount necessary will vary,depending on the subject being treated, the age and general condition ofthe subject to which the macromolecular drug compound is to bedelivered, the capacity of the subject's immune system, the degree ofeffect desired, the severity of the condition being treated, theparticular macromolecular drug compound selected and mode ofadministration of the composition, among other factors. An appropriateeffective amount can be readily determined by one of skill in the art.For example, an effective amount will typically range from about 5 μg toabout 200 mg, in some embodiments from about 5 μg to about 100 mg perday, and in some embodiments, from about 10 μg to about 1 mg of themacromolecular drug compound delivered per day.

Various embodiments of the present invention will now be described inmore detail.

I. Core

As indicated above, the core polymer matrix contains at least polymerthat is generally hydrophobic in nature so that it can retain itsstructural integrity for a certain period of time when placed in anaqueous environment, such as the body of a mammal, and stable enough tobe stored for an extended period before use. Examples of suitablehydrophobic polymers for this purpose may include, for instance,silicone polymer, polyolefins, polyvinyl chloride, polycarbonates,polysulphones, styrene acrylonitrile copolymers, polyurethanes, siliconepolyether-urethanes, polycarbonate-urethanes, siliconepolycarbonate-urethanes, etc., as well as combinations thereof. Ofcourse, hydrophilic polymers that are coated or otherwise encapsulatedwith a hydrophobic polymer are also suitable for use in the core polymermatrix. Typically, the melt flow index of the hydrophobic polymer rangesfrom about 0.2 to about 100 g/10 min, in some embodiments from about 5to about 90 g/10 min, in some embodiments from about 10 to about 80 g/10min, and in some embodiments, from about 30 to about 70 g/10 min, asdetermined in accordance with ASTM D1238-13 at a temperature of 190° C.and a load of 2.16 kilograms.

In certain embodiments, the core polymer matrix may contain asemi-crystalline olefin copolymer. The melting temperature of such anolefin copolymer may, for instance, range from about 40° C. to about140° C., in some embodiments from about 50° C. to about 125° C., and insome embodiments, from about 60° C. to about 120° C., as determined inaccordance with ASTM D3418-15. Such copolymers are generally derivedfrom at least one olefin monomer (e.g., ethylene, propylene, etc.) andat least one polar monomer that is grafted onto the polymer backboneand/or incorporated as a constituent of the polymer (e.g., block orrandom copolymers). Suitable polar monomers include, for instance, avinyl acetate, vinyl alcohol, maleic anhydride, maleic acid,(meth)acrylic acid (e.g., acrylic acid, methacrylic acid, etc.),(meth)acrylate (e.g., acrylate, methacrylate, ethyl acrylate, methylmethacrylate, ethyl methacrylate, etc.), and so forth. A wide variety ofsuch copolymers may generally be employed in the polymer composition,such as ethylene vinyl acetate copolymers, ethylene (meth)acrylic acidpolymers (e.g., ethylene acrylic acid copolymers and partiallyneutralized ionomers of these copolymers, ethylene methacrylic acidcopolymers and partially neutralized ionomers of these copolymers,etc.), ethylene (meth)acrylate polymers (e.g., ethylene methylacrylatecopolymers, ethylene ethyl acrylate copolymers, ethylene butyl acrylatecopolymers, etc.), and so forth. Regardless of the particular monomersselected, the present inventors have discovered that certain aspects ofthe copolymer can be selectively controlled to help achieve the desiredrelease properties. For instance, the polar monomeric content of thecopolymer may be selectively controlled to be within a range of fromabout 10 wt. % to about 60 wt. %, in some embodiments about 20 wt. % toabout 55 wt. %, and in some embodiments, from about 25 wt. % to about 50wt. %. Conversely, the olefin monomeric content of the copolymer may belikewise be within a range of from about 40 wt. % to about 90 wt. %, insome embodiments about 45 wt. % to about 80 wt. %, and in someembodiments, from about 50 wt. % to about 75 wt. %.

In one particular embodiment, for example, the core polymer matrix maycontain an ethylene vinyl acetate polymer, which is a copolymer that isderived from at least one ethylene monomer and at least one vinylacetate monomer. The density of the ethylene vinyl acetate copolymer mayalso range from about 0.900 to about 1.00 gram per cubic centimeter(g/cm³), in some embodiments from about 0.910 to about 0.980 g/cm³, andin some embodiments, from about 0.940 to about 0.970 g/cm³, asdetermined in accordance with ASTM D1505-10. Examples of suitableethylene vinyl acetate copolymers that may be employed include thoseavailable from Celanese under the designation ATEVA® (e.g., ATEVA®4030AC); DuPont under the designation ELVAX® (e.g., ELVAX® 40W); andArkema under the designation EVATANE® (e.g., EVATANE 40-55). Any of avariety of techniques may generally be used to form the ethylene vinylacetate copolymer with the desired properties as is known in the art. Inone embodiment, the polymer is produced by copolymerizing an ethylenemonomer and a vinyl acetate monomer in a high pressure reaction. Vinylacetate may be produced from the oxidation of butane to yield aceticanhydride and acetaldehyde, which can react together to form ethylidenediacetate. Ethylidene diacetate can then be thermally decomposed in thepresence of an acid catalyst to form the vinyl acetate monomer. Examplesof suitable acid catalysts include aromatic sulfonic acids (e.g.,benzene sulfonic acid, toluene sulfonic acid, ethylbenzene sulfonicacid, xylene sulfonic acid, and naphthalene sulfonic acid), sulfuricacid, and alkanesulfonic acids, such as described in U.S. Pat. No.2,425,389 to Oxley et at; U.S. Pat. No. 2,859,241 to Schnizer; and U.S.Pat. No. 4,843,170 to Isshiki et al. The vinyl acetate monomer can alsobe produced by reacting acetic anhydride with hydrogen in the presenceof a catalyst instead of acetaldehyde. This process converts vinylacetate directly from acetic anhydride and hydrogen without the need toproduce ethylidene diacetate. In yet another embodiment, the vinylacetate monomer can be produced from the reaction of acetaldehyde and aketene in the presence of a suitable solid catalyst, such as aperfluorosulfonic acid resin or zeolite.

One or more drug compounds are also be dispersed within the core polymermatrix that are capable of prohibiting and/or treating a condition,disease, and/or cosmetic state a patient. The drug compound may beprophylactically, therapeutically, and/or cosmetically active,systemically or locally. Regardless, at least one drug compound withinthe core is a “macromolecular” compound in the sense that it has a largemolecular weight, such as about 0.5 kilodaltons (“kDa”) or more, in someembodiments about 1 kDa or more, in some embodiments from about 5 kDa toabout 250 kDa, and in some embodiments, from about 20 kDa to about 200kDa. Typically, the bioactivity of such compounds depends upon a uniquethree-dimensional (e.g., folded) structure of the molecule. Thisthree-dimensional molecular structure is substantially maintained byspecific non-covalent bonding interactions, such as hydrogen bonding andhydrophobic bonding interactions between atoms (hydrophobicity). Thedrug compound can be either naturally occurring or man-made by anymethod known in the art. Typically, it is also desired that the drugcompound is stable at high temperatures so that it can be incorporatedinto the polymer matrix at or near the melting temperature of thehydrophobic polymer employed in the core polymer matrix. For example,the drug compound typically remains stable at temperatures of from about25° C. to about 120° C., in some embodiments from about 40° C. to about110° C., in some embodiments from about 40° C. to about 100° C., in someembodiments from about 40° C. to about 80° C., and in some embodiments,from about 50° C. to about 70° C.

Particular examples of suitable macromolecular drug compounds mayinclude, for instance, proteins, peptides, enzymes, antibodies,interferons, interleukins, blood factors, vaccines, nucleotides, lipids,etc., as well as analogues, derivatives, and combinations thereof.Suitable proteins or peptides may include, for instance,adrenocorticotropic hormone, angiotensin, beta-endorphin, bombesin,calcitonin, calcitonin gene relating polypeptide, cholecystokinin-8,colony stimulating factors, desmopressin, endothelin, enkephalin,erythropoietins, gastrins, glucagon, human atrial natriureticpolypeptide, interferons, insulin, growth factors, growth hormones,luteinizing hormone release hormone, melanocyte stimulating hormone,muramyl-dipeptide, neurotensin, oxytocin, parathyroid hormone, peptideT, secretin, somatomedins, somatostatin, thyroid stimulating hormone,thyrotropin releasing hormone, thyrotropin stimulating hormone,vasoactive intestinal polypeptide, vasopressin, etc. Suitable antibodies(e.g., monoclonal antibodies) may include, without limitation, HIVmonoclonal antibody 2F5, rituxumab, infliximab, trastuzumab, adalimumab,omalizumab, tositumomab, efalizumab, and cetuximab. Suitable interferonsmay include interferon alpha-2b, peg interferon alpha-2b, interferonalpha-2b+ribavirin, interferon alpha-2a, pegylated interferon alpha-2a,interferon beta-1a, and interferon beta. Suitable blood factors mayinclude alteplase/tenecteplase and rhesus factor Vila. Suitableinterleukins may include interleukin-2. Suitable vaccines may includewhole viral particles, recombinant proteins, subunit proteins such asgp41, gp120 and gp140, DNA vaccines, plasmids, bacterial vaccines,polysaccharides such as extracellular capsular polysaccharides, andother vaccine vectors. Likewise, suitable nucleic acids may include RNA-or DNA-based molecules, such as oligonucleotides, aptamers, ribozymes,DNAzymes and small interfering RNAs, such as messenger (mRNA), transfer(tRNA), ribosomal (rRNA), interfering (iRNA), small interfering (siRNA),etc.

The core may also optionally contain one or more excipients if sodesired, such as radiocontrast agents, release modifiers, bulkingagents, plasticizers, surfactants, crosslinking agents, flow aids,colorizing agents (e.g., chlorophyll, methylene blue, etc.),antioxidants, stabilizers, lubricants, other types of antimicrobialagents, preservatives, etc. to enhance properties and processability.When employed, the optional excipient(s) typically constitute from about0.01 wt. % to about 20 wt. %, and in some embodiments, from about 0.05wt. % to about 15 wt. %, and in some embodiments, from about 0.1 wt. %to about 10 wt. % of the core. In one embodiment, for instance, aradiocontrast agent may be employed to help ensure that the device canbe detected in an X-ray based imaging technique (e.g., computedtomography, projectional radiography, fluoroscopy, etc.). Examples ofsuch agents include, for instance, barium-based compounds, iodine-basedcompounds, zirconium-based compounds (e.g., zirconium dioxide), etc. Oneparticular example of such an agent is barium sulfate. Other knownantimicrobial agents and/or preservatives may also be employed to helpprevent surface growth and attachment of bacteria, such as metalcompounds (e.g., silver, copper, or zinc), metal salts, quaternaryammonium compounds, etc.

Regardless of the particular components employed, the core may be formedthrough a variety of known techniques, such as by hot-melt extrusion,injection molding, solvent casting, dip coating, spray coating,microextrusion, coacervation, etc. In one embodiment, a hot-meltextrusion technique may be employed. Hot-melt extrusion is generally asolvent-free process in which the components of the core (e.g.,hydrophobic polymer, drug compound(s), optional excipients, etc.) may bemelt blended and optionally shaped in a continuous manufacturing processto enable consistent output quality at high throughput rates. Thistechnique is particularly well suited to various types of hydrophobicpolymers, such as olefin copolymers. Namely, such copolymers typicallyexhibit a relatively high degree of long-chain branching with a broadmolecular weight distribution. This combination of traits can lead toshear thinning of the copolymer during the extrusion process, which helpfacilitates hot-melt extrusion. Furthermore, the polar comonomer units(e.g., vinyl acetate) can serve as an “internal” plasticizer byinhibiting crystallization of the polyethylene chain segments. This maylead to a lower melting point of the olefin copolymer, which improvesthe overall flexibility of the resulting material and enhances itsability to be formed into devices of a wide variety of shapes and sizes.

During a hot-melt extrusion process, melt blending may occur at atemperature range of from about 40° C. to about 200° C., in someembodiments, from about 60° C. to about 180° C., and in someembodiments, from about 80° C. to about 150° C. to form a polymercomposition. Any of a variety of melt blending techniques may generallybe employed. For example, the components may be supplied separately orin combination to an extruder that includes at least one screw rotatablymounted and received within a barrel (e.g., cylindrical barrel). Theextruder may be a single screw or twin screw extruder. For example, oneembodiment of a single screw extruder may contain a housing or barreland a screw rotatably driven on one end by a suitable drive (typicallyincluding a motor and gearbox). If desired, a twin-screw extruder may beemployed that contains two separate screws. The configuration of thescrew is not particularly critical and it may contain any number and/ororientation of threads and channels as is known in the art. For example,the screw typically contains a thread that forms a generally helicalchannel radially extending around a core of the screw. A feed sectionand melt section may be defined along the length of the screw. The feedsection is the input portion of the barrel where the olefin copolymer(s)and/or drug compound(s) are added. The melt section is the phase changesection in which the copolymer is changed from a solid to a liquid-likestate. While there is no precisely defined delineation of these sectionswhen the extruder is manufactured, it is well within the ordinary skillof those in this art to reliably identify the feed section and the meltsection in which phase change from solid to liquid is occurring.Although not necessarily required, the extruder may also have a mixingsection that is located adjacent to the output end of the barrel anddownstream from the melting section. If desired, one or moredistributive and/or dispersive mixing elements may be employed withinthe mixing and/or melting sections of the extruder. Suitabledistributive mixers for single screw extruders may include, forinstance, Saxon, Dulmage, Cavity Transfer mixers, etc. Likewise,suitable dispersive mixers may include Blister ring, Leroy/Maddock, CRDmixers, etc. As is well known in the art, the mixing may be furtherimproved by using pins in the barrel that create a folding andreorientation of the polymer melt, such as those used in Buss Kneaderextruders, Cavity Transfer mixers, and Vortex Intermeshing Pin mixers.

If desired, the ratio of the length (“L”) to diameter (“D”) of the screwmay be selected to achieve an optimum balance between throughput andblending of the components. The L/D value may, for instance, range fromabout 10 to about 50, in some embodiments from about 15 to about 45, andin some embodiments from about 20 to about 40. The length of the screwmay, for instance, range from about 0.1 to about 5 meters, in someembodiments from about 0.4 to about 4 meters, and in some embodiments,from about 0.5 to about 2 meters. The diameter of the screw may likewisebe from about 5 to about 150 millimeters, in some embodiments from about10 to about 120 millimeters, and in some embodiments, from about 20 toabout 80 millimeters. In addition to the length and diameter, otheraspects of the extruder may also be selected to help achieve the desireddegree of blending. For example, the speed of the screw may be selectedto achieve the desired residence time, shear rate, melt processingtemperature, etc. For example, the screw speed may range from about 10to about 800 revolutions per minute (“rpm”), in some embodiments fromabout 20 to about 500 rpm, and in some embodiments, from about 30 toabout 400 rpm. The apparent shear rate during melt blending may alsorange from about 100 seconds⁻¹ to about 10,000 seconds⁻¹, in someembodiments from about 500 seconds⁻¹ to about 5000 seconds⁻¹, and insome embodiments, from about 800 seconds⁻¹ to about 1200 seconds⁻¹. Theapparent shear rate is equal to 4Q/πR³, where Q is the volumetric flowrate (“m³/s”) of the polymer melt and R is the radius (“m”) of thecapillary (e.g., extruder die) through which the melted polymer flows.

Once melt blended together, the resulting polymer composition may be inthe form of pellets, sheets, fibers, filaments, etc., which may beshaped into the core using a variety of known shaping techniques, suchas injection molding, compression molding, nanomolding, overmolding,blow molding, three-dimensional printing, etc. Injection molding may,for example, occur in two main phases—i.e., an injection phase andholding phase. During the injection phase, a mold cavity is filled withthe molten polymer composition. The holding phase is initiated aftercompletion of the injection phase in which the holding pressure iscontrolled to pack additional material into the cavity and compensatefor volumetric shrinkage that occurs during cooling. After the shot hasbuilt, it can then be cooled. Once cooling is complete, the moldingcycle is completed when the mold opens and the part is ejected, such aswith the assistance of ejector pins within the mold. Any suitableinjection molding equipment may generally be employed in the presentinvention. In one embodiment, an injection molding apparatus may beemployed that includes a first mold base and a second mold base, whichtogether define a mold cavity having the shape of the core. The moldingapparatus includes a resin flow path that extends from an outer exteriorsurface of the first mold half through a sprue to a mold cavity. Thepolymer composition may be supplied to the resin flow path using avariety of techniques. For example, the composition may be supplied(e.g., in the form of pellets) to a feed hopper attached to an extruderbarrel that contains a rotating screw (not shown). As the screw rotates,the pellets are moved forward and undergo pressure and friction, whichgenerates heat to melt the pellets. A cooling mechanism may also beprovided to solidify the resin into the desired shape of the core (e.g.,disc, rod, etc.) within the mold cavity. For instance, the mold basesmay include one or more cooling lines through which a cooling mediumflows to impart the desired mold temperature to the surface of the moldbases for solidifying the molten material. The mold temperature (e.g.,temperature of a surface of the mold) may range from about 50° C. toabout 120° C., in some embodiments from about 60° C. to about 110° C.,and in some embodiments, from about 70° C. to about 90° C.

As indicated above, another suitable technique for forming a core of thedesired shape and size is three-dimensional printing. During thisprocess, the polymer composition may be incorporated into a printercartridge that is readily adapted for use with a printer system. Theprinter cartridge may, for example, contains a spool or other similardevice that carries the polymer composition. When supplied in the formof filaments, for example, the spool may have a generally cylindricalrim about which the filaments are wound. The spool may likewise define abore or spindle that allows it to be readily mounted to the printerduring use. Any of a variety of three-dimensional printer systems can beemployed in the present invention. Particularly suitable printer systemsare extrusion-based systems, which are often referred to as “fuseddeposition modeling” systems. For example, the polymer composition maybe supplied to a build chamber of a print head that contains a platenand gantry. The platen may move along a vertical z-axis based on signalsprovided from a computer-operated controller. The gantry is a guide railsystem that may be configured to move the print head in a horizontal x-yplane within the build chamber based on signals provided fromcontroller. The print head is supported by the gantry and is configuredfor printing the build structure on the platen in a layer-by-layermanner, based on signals provided from the controller. For example, theprint head may be a dual-tip extrusion head.

II. Membrane Layer

As indicated above, the implantable device contains at least onemembrane layer that is positioned adjacent to an outer surface of acore. The number of membrane layers may vary depending on the particularconfiguration of the device, the nature of the drug compound, and thedesired release profile. For example, the device may contain only onemembrane layer. Referring to FIGS. 1-2 , for example, one embodiment ofan implantable device 10 is shown that contains a core 40 having agenerally circular cross-sectional shape and is elongated so that theresulting device is generally cylindrical in nature. The core 40 definesan outer circumferential surface 61 about which a membrane layer 20 iscircumferentially disposed. Similar to the core 40, the membrane layer20 also has a generally circular cross-sectional shape and is elongatedso that it covers the entire length of the core 40. During use of thedevice 10, a drug compound is capable of being released from the core 40and through the membrane layer 20 so that it exits from an externalsurface 21 of the device.

Of course, in other embodiments, the device may contain multiplemembrane layers. In the device of FIGS. 1-2 , for example, one or moreadditional membrane layers (not shown) may be disposed over the membranelayer 20 to help further control release of the drug compound. In otherembodiments, the device may be configured so that the core is positionedor sandwiched between separate membrane layers. Referring to FIGS. 3-4 ,for example, one embodiment of an implantable device 100 is shown thatcontains a core 140 having a generally circular cross-sectional shapeand is elongated so that the resulting device is generally disc-shapedin nature. The core 140 defines an upper outer surface 161 on which ispositioned a first membrane layer 120 and a lower outer surface 163 onwhich is positioned a second membrane layer 122. Similar to the core140, the first membrane layer 120 and the second membrane layer 122 alsohave a generally circular cross-sectional shape that generally coversthe core 140. If desired, edges of the membrane layers 120 and 122 mayalso extend beyond the periphery of the core 140 so that they can besealed together to cover any exposed areas of an externalcircumferential surface 170 of the core 140. During use of the device100, a drug compound is capable of being released from the core 140 andthrough the first membrane layer 120 and second membrane layer 122 sothat it exits from external surfaces 121 and 123 of the device. Ofcourse, if desired, one or more additional membrane layers (not shown)may also be disposed over the first membrane layer 120 and/or secondmembrane layer 122 to help further control release of the drug compound.

Regardless of the particular configuration employed, the membranelayer(s) generally contain a membrane polymer matrix that contains ahydrophobic polymer and hydrophilic compound, such as described above.The polymer matrix typically constitutes from about 30 wt. % to 100 wt.%, in some embodiments, from about 40 wt. % to about 99 wt. %, and insome embodiments, from about 50 wt. % to about 90 wt. % of a membranelayer. As indicated above, the weight ratio of the hydrophobic polymersto the hydrophilic compounds within the membrane polymer matrix mayrange from about 0.8 to about 20, in some embodiments from about 1 toabout 16, and in some embodiments, from about 1.2 to about 10. Suchhydrophilic compounds may, for example, constitute from about 1 wt. % toabout 50 wt. %, in some embodiments from about 2 wt. % to about 40 wt.%, and in some embodiments, from about 5 wt. % to about 30 wt. % of themembrane polymer matrix, while hydrophobic polymers typically constitutefrom about 50 wt. % to about 99 wt. %, in some embodiments from about 60wt. % to about 98 wt. %, and in some embodiments, from about 70 wt. % toabout 95 wt. % of the membrane polymer matrix. In such embodiments,hydrophilic compounds may likewise constitute from about 1 wt. % toabout 50 wt. %, in some embodiments from about 2 wt. % to about 40 wt.%, and in some embodiments, from about 5 wt. % to about 30 wt. % of amembrane layer. Suitable hydrophilic compounds may include, forinstance, polymers, non-polymeric materials (e.g., glycerin, sugars,salts, peptides, etc.), etc. Examples of suitable hydrophilic polymersinclude, for instance, sodium, potassium and calcium alginates,carboxymethylcellulose, agar, gelatin, polyvinyl alcohols, polyalkyleneglycols (e.g., polyethylene glycol), collagen, pectin, chitin, chitosan,poly-1-caprolactone, polyvinylpyrrolidone,poly(vinylpyrrolidone-co-vinyl acetate), polysaccharides, hydrophilicpolyurethane, polyhydroxyacrylate, dextran, xanthan, hydroxypropylcellulose, methylcellulose, proteins, ethylene vinyl alcohol copolymers,water-soluble polysilanes and silicones, water-soluble polyurethanes,etc., as well as combinations thereof. Particularly suitable hydrophilicpolymers are polyalkylene glycols, such as those having a molecularweight of from about 100 to 500,000 grams per mole, in some embodimentsfrom about 500 to 200,000 grams per mole, and in some embodiments, fromabout 1,000 to about 100,000 grams per mole. Specific examples of suchpolyalkylene glycols include, for instance, polyethylene glycols,polypropylene glycols polytetramethylene glycols, polyepichlorohydrins,etc.

When employing multiple membrane layers, it is typically desired thateach membrane layer contains a polymer matrix that includes ahydrophobic polymer and hydrophilic compound. For example, a firstmembrane layer may contain a first membrane polymer matrix and a secondmembrane layer may contain a second membrane polymer matrix. In suchembodiments, the first and second polymer matrices each contain ahydrophobic polymer and hydrophilic compound. The hydrophilic compoundand hydrophobic polymer within one membrane layer may be the same ordifferent than those employed in another membrane layer. In oneembodiment, for instance, both the first and second polymer matricesemploy the same hydrophilic compound (e.g., hydrophilic polymer) andhydrophobic polymer (e.g., α-olefin copolymer). Likewise, thehydrophobic polymer used in the membrane layer(s) may also be the sameor different the hydrophobic polymer employed in the core. In oneembodiment, for instance, both the core and the membrane layer(s) employthe same hydrophobic polymer (e.g., α-olefin copolymer). In yet otherembodiments, the membrane layer(s) may employ a hydrophobic polymer(e.g., α-olefin copolymer) that has a lower melt flow index than apolymer employed in the core. Among other things, this can further helpcontrol the release of the drug compound from the device. For example,the ratio of the melt flow index of a hydrophobic polymer employed inthe core to the melt flow index of a hydrophobic polymer employed in themembrane layer(s) may be from about 1 to about 20, in some embodimentsabout 2 to about 15, and in some embodiments, from about 4 to about 12.The melt flow index of the hydrophobic polymer in the membrane layer(s)may, for example, range from about 1 to about 80 g/10 min, in someembodiments from about 2 to about 70 g/10 min, and in some embodiments,from about 5 to about 60 g/10 min, as determined in accordance with ASTMD1238-13 at a temperature of 190° C. and a load of 2.16 kilograms.Examples of suitable ethylene vinyl acetate copolymers that may beemployed include those available from Celanese under the designationATEVA® (e.g., ATEVA® 4030AC or 2861A).

As indicated above, the membrane layer(s) used in the device mayoptionally contain a macromolecular drug compound, such as describedabove, which is dispersed within the polymer matrix. The drug compoundin the membrane layer(s) may be the same or different than the drugcompound employed in the core. Regardless, when such a macromoleculardrug compound is employed in a membrane layer, the membrane layergenerally contains the drug compound in an amount such that the ratio ofthe concentration (wt. %) of the drug compound in the core to theconcentration (wt. %) of the drug compound in the membrane layer isgreater than 1, in some embodiments about 1.5 or more, and in someembodiments, from about 1.8 to about 4. When employed, drug compoundstypically constitute only from about 1 wt. % to about 40 wt. %, in someembodiments from about 5 wt. % to about 35 wt. %, and in someembodiments, from about 10 wt. % to about 30 wt. % of a membrane layer.Of course, in other embodiments, the membrane layer is generally free ofsuch macromolecular drug compounds prior to release from the core. Whenmultiple membrane layers are employed, each membrane layer may generallycontains the drug compound in an amount such that the ratio of theweight percentage of the drug compound in the core to the weightpercentage of the drug compound in the membrane layer is greater than 1,in some embodiments about 1.5 or more, and in some embodiments, fromabout 1.8 to about 4.

The membrane layer(s) and/or the core may also optionally contain one ormore excipients as described above, such as radiocontrast agents,bulking agents, plasticizers, surfactants, crosslinking agents, flowaids, colorizing agents (e.g., chlorophyll, methylene blue, etc.),antioxidants, stabilizers, lubricants, other types of antimicrobialagents, preservatives, etc. to enhance properties and processability.When employed, the optional excipient(s) typically constitute from about0.01 wt. % to about 60 wt. %, and in some embodiments, from about 0.05wt. % to about 50 wt. %, and in some embodiments, from about 0.1 wt. %to about 40 wt. % of a membrane layer.

One or more nonionic, anionic, and/or amphoteric surfactants may also beemployed to help create a uniform dispersion. When employed, suchsurfactant(s) typically constitute from about 0.05 wt. % to about 8 wt.%, and in some embodiments, from about 0.1 wt. % to about 6 wt. %, andin some embodiments, from about 0.5 wt. % to about 3 wt. % of the core.Nonionic surfactants, which typically have a hydrophobic base (e.g.,long chain alkyl group or an alkylated aryl group) and a hydrophilicchain (e.g., chain containing ethoxy and/or propoxy moieties), areparticularly suitable. Some suitable nonionic surfactants that may beused include, but are not limited to, ethoxylated alkylphenols,ethoxylated and propoxylated fatty alcohols, polyethylene glycol ethersof methyl glucose, polyethylene glycol ethers of sorbitol, ethyleneoxide-propylene oxide block copolymers, ethoxylated esters of fatty(C₈-C₁₈) acids, condensation products of ethylene oxide with long chainamines or amides, condensation products of ethylene oxide with alcohols,fatty acid esters, monoglyceride or diglycerides of long chain alcohols,and mixtures thereof. Particularly suitable nonionic surfactants mayinclude ethylene oxide condensates of fatty alcohols, polyoxyethyleneethers of fatty acids, polyoxyethylene sorbitan fatty acid esters, andsorbitan fatty acid esters, etc. The fatty components used to form suchemulsifiers may be saturated or unsaturated, substituted orunsubstituted, and may contain from 6 to 22 carbon atoms, in someembodiments from 8 to 18 carbon atoms, and in some embodiments, from 12to 14 carbon atoms. Sorbitan fatty acid esters (e.g., monoesters,diester, triesters, etc.) that have been modified with polyoxyethyleneare one particularly useful group of nonionic surfactants. Thesematerials are typically prepared through the addition of ethylene oxideto a 1,4-sorbitan ester. The addition of polyoxyethylene converts thelipophilic sorbitan ester surfactant to a hydrophilic surfactant that isgenerally soluble or dispersible in water. Such materials arecommercially available under the designation TWEEN® (e.g., TWEEN® 80, orpolyethylene (20) sorbitan monooleate).

The membrane layer(s) may be formed using the same or a differenttechnique than used to form the core, such as by hot-melt extrusion,injection molding, solvent casting, dip coating, spray coating,microextrusion, coacervation, etc. In one embodiment, a hot-meltextrusion technique may be employed. The core and membrane layer(s) mayalso be formed separately or simultaneously. In one embodiment, forinstance, the core and membrane layer(s) are separately formed and thencombined together using a known bonding technique, such as by stamping,hot sealing, adhesive bonding, etc.

III. Use of Device

The implantable device of the present invention may be used in a varietyof different ways to treat prohibit and/or treat a condition, disease,or cosmetic state in a patient. The device may be implantedsubcutaneously, orally, mucosally, etc., using standard techniques. Thedelivery route may be intrapulmonary, gastroenteral, subcutaneous,intramuscular, or for introduction into the central nervous system,intraperitoneum or for intraorgan delivery. If desired, the device maybe sealed within a package (e.g., sterile blister package) prior to use.The materials and manner in which the package is sealed may vary as isknown in the art. In one embodiment, for instance, the package maycontain a substrate that includes any number of layers desired toachieve the desired level of protective properties, such as 1 or more,in some embodiments from 1 to 4 layers, and in some embodiments, from 1to 3 layers. Typically, the substrate contains a polymer film, such asthose formed from a polyolefin (e.g., ethylene copolymers, propylenecopolymers, propylene homopolymers, etc.), polyester (e.g., polyethyleneterephthalate, polyethylene naphthalate, polybutylene terephthalate,etc.), vinyl chloride polymer, vinyl chloridine polymer, ionomer, etc.,as well as combinations thereof. One or multiple panels of the film maybe sealed together (e.g., heat sealed), such as at the peripheral edges,to form a cavity within which the device may be stored. For example, asingle film may be folded at one or more points and sealed along itsperiphery to define the cavity within with the device is located. To usethe device, the package may be opened, such as by breaking the seal, andthe device may then be removed and implanted into a patient.

The present invention may be better understood with reference to thefollowing examples.

Test Methods

Drug Release:

The release of a drug compound (e.g., bromelain) may be determined usingan in vitro method. More particularly, implantable device samples may beplaced in 150 milliliters of an aqueous sodium azide solution. Thesolutions are enclosed in UV-protected, 250-ml Duran® flasks. The flasksare then placed into a temperature-controlled water bath andcontinuously shaken at 100 rpm. A temperature of 37° C. is maintainedthrough the release experiments to mimic in vivo conditions. Samples aretaken in regular time intervals by completely exchanging the aqueoussodium azide solution. The concentration of the drug compound insolution is determined via UV/Vis absorption spectroscopy using a Cary 1split beam instrument. From this data, the amount of the drug compoundreleased per sampling interval (microgram per hour) is calculated andplotted over time (hours). Further, the cumulative release ratio of thedrug compound is also calculated as a percentage by dividing the amountof the drug compound released at each sampling interval by the totalamount of drug compound initially present, and then multiplying thisnumber by 100. This percentage is then plotted over time (hours).

EXAMPLES 1-4

Four (4) different types of core layers are formed with varyingconcentrations of a hydrophobic polymer (Ateva® 4030AC) and amacromolecular biologic (bromelain). To form the samples, bromelainpowder is initially melt compounded into Ateva® 4030AC using a HaakeRheomix 600p. First, the Rheomix 600p chamber is filled with Ateva®4030AC pellets and compounded for 8 minutes at 50° C. The compounding inthe Rheomix 600p is done at 50 rpm using roller-type rotors. After 8minutes, the bromelain powder is added to the Ateva® 4030AC melt andmelt mixing continues for 3 minutes at 50° C. After melt mixing, theblend is taken out of the Rheomix 600p and pressed into 1 mm thicksheets using a thermal press. The temperature during pressing is 50° C.,the pressing time is 3 minutes, and the pressure is 100 bar. To avoidadhesion of the molten EVA film to the surfaces of the press, alow-adhesion, temperature-tolerant polyester foil (Hostaphan® RNK 23) isplaced between the EVA blend and the press plates. After cool down, thepolyester films are removed. Discs having a diameter of 25 millimetersare stamped out of the EVA-bromelain sheet using a punching press tocreate the bromelain containing core layer/monolithic bromelainimplants.

The bromelain and Ateva® 4030AC contents inside the different corelayers are given in Table 1.

TABLE 1 Example Ateva ® 4030AC (wt. %) Bromelain (wt. %) 1 80 20 2 60 403 40 60 4 20 80

Once formed, the samples were tested for their release rate as describedabove. The results are set forth in FIGS. 5-6 .

EXAMPLES 5-7

Three (3) different types of core-membrane implantable devices areformed using a core layer containing 20 wt. % of a hydrophobic polymerand 80 wt. % of a biologic in combination with varying concentrations ofcomponents in the membrane layers. The core layer is formed by meltcompounding bromelain powder into Ateva® 4030AC using a Haake Rheomix600p. First, the Rheomix 600p chamber is filled with Ateva® 4030ACpellets and compounded for 8 minutes at 50° C. The compounding in theRheomix 600p is done at 50 rpm using roller-type rotors. After 8minutes, the bromelain powder is added to the Ateva® 4030AC melt andmelt mixing continues for 3 minutes at 50° C. After melt mixing, theblend is taken out of the Rheomix 600p and pressed into 1 mm thicksheets using a thermal press. The temperature during pressing is 50° C.,the pressing time is 3 minutes, and the pressure is 100 bar. To avoidadhesion of the molten EVA film to the surfaces of the press, alow-adhesion, temperature-tolerant polyester foil (Hostaphan® RNK 23) isplaced between the EVA blend and the press plates. After cool down, thepolyester films are removed. Discs having a diameter of 23 millimetersare stamped out of the EVA-bromelain sheet using a punching press tocreate the bromelain containing core layer/monolithic bromelainimplants. The membrane layers are formed by melt compounding Ateva®4030AC and Luviskol® VA64 using a Haake Rheomix 600p in the same manneras described above, except that the resulting discs had a diameter of 25millimeters. To form the core-membrane implants, a solvent bondingtechnique is employed. That is, a small amount of toluene is applied onthe sides of the discs using a paintbrush and then immediatelythereafter the sandwiched layers are bonded and pressed together.Pressure is maintained for a period of 24 hours as the toluene isallowed to evaporate. After this time period, the edge of the core layeris sealed using a highly concentrated toluene solution of Ateva® 4030ACapplied from a plastic pipette. The edges are allowed to dry fromtoluene for a time period of at least 48 hours. Table 2 shows thecontent of the core and membrane layers used in each Example.

TABLE 2 Core Layer 2 Membrane Layers (1 mm × 23 mm) (1 mm × 25 mm)Ateva ® Ateva ® 4030AC Bromelain 4030AC Luviskol ® VA64 Example (wt. %)(wt. %) (wt. %) (wt. %) 5 20 80 80 20 6 20 80 60 40 7 20 80 40 60

Once formed, the samples were tested for their release rate as describedabove. The results are set forth in FIGS. 7-8 .

EXAMPLES 8-13

Six (6) different types of core-membrane implantable devices are formedusing a core layer containing 40 wt. % of a hydrophobic polymer and 60wt. % of a biologic in combination with varying concentrations ofcomponents in the membrane layers. The core layer is formed by meltcompounding bromelain powder into Ateva® 4030AC using a Haake Rheomix600p. First, the Rheomix 600p chamber is filled with Ateva® 4030ACpellets and compounded for 8 minutes at 50° C. The compounding in theRheomix 600p is done at 50 rpm using roller-type rotors. After 8minutes, the bromelain powder is added to the Ateva® 4030AC melt andmelt mixing continues for 3 minutes at 50° C. After melt mixing, theblend is taken out of the Rheomix 600p and pressed into 1 mm thicksheets using a thermal press. The temperature during pressing is 50° C.,the pressing time is 3 minutes, and the pressure is 100 bar. To avoidadhesion of the molten EVA film to the surfaces of the press, alow-adhesion, temperature-tolerant polyester foil (Hostaphan® RNK 23) isplaced between the EVA blend and the press plates. After cool down, thepolyester films are removed. Discs having a diameter of 23 millimetersare stamped out of the EVA-bromelain sheet using a punching press tocreate the bromelain containing core layer/monolithic bromelainimplants. The membrane layers are formed by melt compounding Ateva®2861A and polyethylene glycol (“PEG”) having a molecular weight of100,000 grams per mole using a Haake Rheomix 600p in the same manner asdescribed above, except that compounding occurred at a temperature of170° C. and the resulting discs had a thickness of 0.5 millimeters and adiameter of 25 millimeters. To form the core-membrane implants, asolvent bonding technique is employed. That is, a small amount oftoluene is applied on the sides of the discs using a paintbrush and thenimmediately thereafter the sandwiched layers are bonded and pressedtogether. Pressure is maintained for a period of 24 hours as the tolueneis allowed to evaporate. After this time period, the edge of the corelayer is sealed using a highly concentrated toluene solution of Ateva®4030AC applied from a plastic pipette. The edges are allowed to dry fromtoluene for a time period of at least 48 hours. Table 3 shows thecontent of the core and membrane layers used in each Example.

TABLE 3 Core Layer 2 Membrane Layers (1 mm × 23 mm) (0.5 mm × 25 mm)Ateva ® 4030AC Bromelain Ateva ® 2861A PEG Example (wt. %) (wt. %) (wt.%) (wt. %) 8 40 60 99 1 9 40 60 95 5 10 40 60 90 10 11 40 60 75 25 12 4060 70 30 13 40 60 65 35

Once formed, the samples were tested for their release rate as describedabove. The results are set forth in FIGS. 9-10 .

EXAMPLES 14-18

Five (5) different types of core-membrane implantable devices are formedusing a core layer containing 40 wt. % of a hydrophobic polymer and 60wt. % of a biologic in combination with varying concentrations ofcomponents in the membrane layers. The core layer is formed by meltcompounding bromelain powder into Ateva® 4030AC using a Haake Rheomix600p. First, the Rheomix 600p chamber is filled with Ateva® 4030ACpellets and compounded for 8 minutes at 50° C. The compounding in theRheomix 600p is done at 50 rpm using roller-type rotors. After 8minutes, the bromelain powder is added to the Ateva® 4030AC melt andmelt mixing continues for 3 minutes at 50° C. After melt mixing, theblend is taken out of the Rheomix 600p and pressed into 1 mm thicksheets using a thermal press. The temperature during pressing is 50° C.,the pressing time is 3 minutes, and the pressure is 100 bar. To avoidadhesion of the molten EVA film to the surfaces of the press, alow-adhesion, temperature-tolerant polyester foil (Hostaphan® RNK 23) isplaced between the EVA blend and the press plates. After cool down, thepolyester films are removed. Discs having a diameter of 23 millimetersare stamped out of the EVA-bromelain sheet using a punching press tocreate the bromelain containing core layer/monolithic bromelainimplants. The membrane layers are formed by melt compounding Ateva®2861A and Luviskol® VA64 using a Haake Rheomix 600p in the same manneras described above, except that compounding occurred at a temperature of170° C., the temperature used during pressing was 100° C., and theresulting discs had a thickness of 0.5 millimeters and a diameter of 25millimeters. To form the core-membrane implants, a solvent bondingtechnique is employed. That is, a small amount of toluene is applied onthe sides of the discs using a paintbrush and then immediatelythereafter the sandwiched layers are bonded and pressed together.Pressure is maintained for a period of 24 hours as the toluene isallowed to evaporate. After this time period, the edge of the core layeris sealed using a highly concentrated toluene solution of Ateva® 4030ACapplied from a plastic pipette. The edges are allowed to dry fromtoluene for a time period of at least 48 hours. Table 4 shows thecontent of the core and membrane layers used in each Example.

TABLE 4 Core Layer 2 Membrane Layers (1 mm × 23 mm) (0.5 mm × 25 mm)Ateva ® Ateva ® 4030AC Bromelain 2861A Luviskol ® VA64 Example (wt. %)(wt. %) (wt. %) (wt. %) 14 40 60 99 1 15 40 60 95 5 16 40 60 90 10 17 4060 75 25 18 40 60 50 50

Once formed, the samples were tested for their release rate as describedabove. The results are set forth in FIGS. 11-12 .

EXAMPLES 19-20

Two (2) different types of core-membrane implantable devices are formedusing a core layer containing 40 wt. % of a hydrophobic polymer and 60wt. % of a biologic in combination with varying concentrations ofcomponents in the membrane layers. The core layer is formed by meltcompounding bromelain powder into Ateva® 4030AC using a Haake Rheomix600p. First, the Rheomix 600p chamber is filled with Ateva® 4030ACpellets and compounded for 8 minutes at 50° C. The compounding in theRheomix 600p is done at 50 rpm using roller-type rotors. After 8minutes, the bromelain powder is added to the Ateva® 4030AC melt andmelt mixing continues for 3 minutes at 50° C. After melt mixing, theblend is taken out of the Rheomix 600p and pressed into 1 mm thicksheets using a thermal press. The temperature during pressing is 50° C.,the pressing time is 3 minutes, and the pressure is 100 bar. To avoidadhesion of the molten EVA film to the surfaces of the press, alow-adhesion, temperature-tolerant polyester foil (Hostaphan® RNK 23) isplaced between the EVA blend and the press plates. After cool down, thepolyester films are removed. Discs having a diameter of 23 millimetersare stamped out of the EVA-bromelain sheet using a punching press tocreate the bromelain containing core layer/monolithic bromelainimplants. The membrane layers are formed by melt compounding Ateva®4030AC, polyethylene glycol (“PEG”) having a molecular weight of 100,000grams per mole, and bromelain powder using a Haake Rheomix 600p in thesame manner as described above, except that the resulting discs had adiameter of 25 millimeters. To form the core-membrane implants, asolvent bonding technique is employed. That is, a small amount oftoluene is applied on the sides of the discs using a paintbrush and thenimmediately thereafter the sandwiched layers are bonded and pressedtogether. Pressure is maintained for a period of 24 hours as the tolueneis allowed to evaporate. After this time period, the edge of the corelayer is sealed using a highly concentrated toluene solution of Ateva®4030AC applied from a plastic pipette. The edges are allowed to dry fromtoluene for a time period of at least 48 hours. Table 5 shows thecontent of the core and membrane layers used in each Example.

TABLE 5 Core Layer 2 Membrane Layers (1 mm × 23 mm) (1 mm × 25 mm)Ateva ® Ateva ® 4030AC Bromelain 4030AC Bromelain PEG Example (wt. %)(wt. %) (wt. %) (wt. %) (wt. %) 19 40 60 75 20 5 20 40 60 60 20 20

Once formed, the samples were tested for their release rate as describedabove. The results are set forth in FIGS. 13-14 .

EXAMPLES 21-23

Three (3) different types of core-membrane implantable devices areformed using a core layer containing 40 wt. % of a hydrophobic polymerand 60 wt. % of a biologic in combination with varying concentrations ofcomponents in the membrane layers. The core layer is formed by meltcompounding bromelain powder into Ateva® 4030AC using a Haake Rheomix600p. First, the Rheomix 600p chamber is filled with Ateva® 4030ACpellets and compounded for 8 minutes at 50° C. The compounding in theRheomix 600p is done at 50 rpm using roller-type rotors. After 8minutes, the bromelain powder is added to the Ateva® 4030AC melt andmelt mixing continues for 3 minutes at 50° C. After melt mixing, theblend is taken out of the Rheomix 600p and pressed into 1 mm thicksheets using a thermal press. The temperature during pressing is 50° C.,the pressing time is 3 minutes, and the pressure is 100 bar. To avoidadhesion of the molten EVA film to the surfaces of the press, alow-adhesion, temperature-tolerant polyester foil (Hostaphan® RNK 23) isplaced between the EVA blend and the press plates. After cool down, thepolyester films are removed. Discs having a diameter of 23 millimetersare stamped out of the EVA-bromelain sheet using a punching press tocreate the bromelain containing core layer/monolithic bromelainimplants. The membrane layers are formed by melt compounding Ateva®4030AC and polyethylene glycol (“PEG”) having a molecular weight of100,000 grams per mole using a Haake Rheomix 600p in the same manner asdescribed above, except that compounding occurred at a temperature of50° C., the temperature used during pressing was 80° C., and theresulting discs had a thickness of 0.5 millimeters and a diameter of 25millimeters. To form the core-membrane implants, a solvent bondingtechnique is employed. That is, a small amount of toluene is applied onthe sides of the discs using a paintbrush and then immediatelythereafter the sandwiched layers are bonded and pressed together.Pressure is maintained for a period of 24 hours as the toluene isallowed to evaporate. After this time period, the edge of the core layeris sealed using a highly concentrated toluene solution of Ateva® 4030ACapplied from a plastic pipette. The edges are allowed to dry fromtoluene for a time period of at least 48 hours.

TABLE 6 Core Layer 2 Membrane Layers (1 mm × 23 mm) (0.5 mm × 25 mm)Ateva ® 4030AC Bromelain Ateva ® 4030AC PEG Example (wt. %) (wt. %) (wt.%) (wt. %) 21 40 60 95 5 22 40 60 80 20 23 40 60 70 30

Once formed, the samples were tested for their release rate as describedabove. The results are set forth in FIGS. 15-16 .

EXAMPLES 24-27

Four (4) different types of core-membrane implantable devices are formedusing a core layer containing 40 wt. % of a hydrophobic polymer and 60wt. % of a biologic in combination with varying concentrations ofcomponents in the membrane layers. The core layer is formed by meltcompounding collagen powder into Ateva® 4030AC using a Haake Rheomix600p. First, the Rheomix 600p chamber is filled with Ateva® 4030ACpellets and compounded for 8 minutes at 50° C. The compounding in theRheomix 600p is done at 50 rpm using roller-type rotors. After 8minutes, the collagen powder is added to the Ateva® 4030AC melt and meltmixing continues for 3 minutes at 50° C. After melt mixing, the blend istaken out of the Rheomix 600p and pressed into 1 mm thick sheets using athermal press. The temperature during pressing is 50° C., the pressingtime is 3 minutes, and the pressure is 100 bar. To avoid adhesion of themolten EVA film to the surfaces of the press, a low-adhesion,temperature-tolerant polyester foil (Hostaphan® RNK 23) is placedbetween the EVA blend and the press plates. After cool down, thepolyester films are removed. Discs having a diameter of 23 millimetersare stamped out of the EVA-collagen sheet using a punching press tocreate the collagen containing core layer/monolithic collagen implants.The membrane layers are formed by melt compounding Ateva® 4030AC andLuviskol® VA64 using a Haake Rheomix 600p in the same manner asdescribed above, except that compounding occurred at a temperature of50° C., the temperature used during pressing was 50° C., and theresulting discs had a thickness of 1.0 millimeters and a diameter of 25millimeters. To form the core-membrane implants, a solvent bondingtechnique is employed. That is, a small amount of toluene is applied onthe sides of the discs using a paintbrush and then immediatelythereafter the sandwiched layers are bonded and pressed together.Pressure is maintained for a period of 24 hours as the toluene isallowed to evaporate. After this time period, the edge of the core layeris sealed using a highly concentrated toluene solution of Ateva® 4030ACapplied from a plastic pipette. The edges are allowed to dry fromtoluene for a time period of at least 48 hours. Table 7 shows thecontent of the core and membrane layers used in each Example.

TABLE 7 Core Layer 2 Membrane Layers (1 mm × 23 mm) (1 mm × 25 mm)Ateva ® Ateva ® 4030AC Collagen 4030AC Luviskol ® VA64 Example (wt. %)(wt. %) (wt. %) (wt. %) 24 40 60 75 25 25 40 60 70 30 26 40 60 65 35 2740 60 60 40

Once formed, the samples were tested for their release rate as describedabove. The results are set forth in FIGS. 17-18 .

EXAMPLES 28-30

Three (3) different types of core-membrane implantable devices areformed using a core layer containing 40 wt. % of a hydrophobic polymerand 60 wt. % of a biologic in combination with varying with varyingconcentrations of components in the membrane layers. The core rod isformed by melt compounding bromelain powder into Ateva® 4030AC using aDSM bench top double-screw extruder with conical, intermeshing screws.First, Ateva® 4030AC (1 mm fine powder) is dry blended with bromelain.The blended mixture is then fed into the DSM extruder. The extrusiontemperature was 60° C. and the screw speed was 50 rpm. The extrudedfilament is allowed to cool down to room temperature and then cut into30 mm long rods. The diameter of the extruded filament was 3.4 mm. Themembrane layer is formed by melt compounding Luviskol® VA64 powder intoAteva® 4030AC using a Haake Rheomix 600p. First, the Rheomix 600pchamber is filled with Ateva® 4030AC pellets and compounded for 8minutes at 50° C. The compounding in the Rheomix 600p is done at 50 rpmusing roller-type rotors. After 8 minutes, the Luviskol® VA64 powder isadded to the Ateva® 4030AC melt and melt mixing continues for 3 minutesat 50° C. After melt mixing, the blend is taken out of the Rheomix 600pand pressed into 1 mm thick sheets using a thermal press. Thetemperature during pressing is 50° C., the pressing time is 3 minutes,and the pressure is 100 bar.

To avoid adhesion of the molten Ateva® 4030AC film to the surfaces ofthe press, a low-adhesion, temperature-tolerant polyester foil(Hostaphan® RNK 23) is placed between the Ateva® 4030AC blend and thepress plates. After cool down, the polyester films are removed. To formthe core-membrane implants, a temperature bonding technique is employed.That is the membrane layers and the core rods are heated to 55° C. for30 minutes. A single membrane layer is then attached to a single corerod manually by applying gentle pressure while rolling the specimen fora prolonged period of time. After this, both ends of the cylinders andthe seam between the ends of the membrane layer are sealed using ahighly concentrated toluene solution of Ateva® 4030AC applied from aplastic pipette. The edges and the seam are allowed to dry from toluenefor a time period of at least 48 hours. Table 8 shows the content of thecore and membrane layers used in each Example.

TABLE 8 Core Rod (diameter 3.4 mm; Membrane Layer length 30 mm)(thickness: 1 mm) Ateva ® Ateva ® 4030AC Bromelain 4030AC Luviskol ®VA64 Example (wt. %) (wt. %) (wt. %) (wt. %) 28 40 60 80 20 29 40 60 7030 30 40 60 60 40

Once formed, the samples were tested for their release rate as describedabove. The results are set forth in FIGS. 19-20 .

These and other modifications and variations of the present inventionmay be practiced by those of ordinary skill in the art, withoutdeparting from the spirit and scope of the present invention. Inaddition, it should be understood that aspects of the variousembodiments may be interchanged both in whole or in part. Furthermore,those of ordinary skill in the art will appreciate that the foregoingdescription is by way of example only, and is not intended to limit theinvention so further described in such appended claims.

What is claimed is:
 1. An implantable device for delivery of amacromolecular drug compound, the device comprising: a core having anouter surface, wherein the core comprises a core polymer matrix withinwhich is dispersed a drug compound having a molecular weight of about0.5 kDa or more, the polymer matrix containing a first ethylene vinylacetate copolymer having a melting temperature of from about 40° C. toabout 60° C. as determined in accordance with ASTM D3418-15; and amembrane layer positioned adjacent to the outer surface of the core,wherein the membrane layer comprises a membrane polymer matrix withinwhich the macromolecular drug compound is optionally dispersed, whereinthe membrane polymer matrix contains a second ethylene vinyl acetatecopolymer having a melting temperature of from about 40° C. to about 60°C. as determined in accordance with ASTM D3418-15 in combination with ahydrophilic compound, wherein the weight ratio of the second ethylenevinyl acetate copolymer to the hydrophilic compound within the membranepolymer matrix ranges from at least about 2.3 to about
 99. 2. Theimplantable device of claim 1, wherein the device has a generallycircular cross-sectional shape.
 3. The implantable device of claim 2,wherein the device has a diameter of from about 0.5 to about 50millimeters.
 4. The implantable device of claim 1, wherein the device isin the form of a cylinder.
 5. The implantable device of claim 1, whereinthe device is in the form of a disc.
 6. The implantable device of claim1, wherein macromolecular drug compounds constitute from about 5 wt. %to about 60 wt. % of the core and the core polymer matrix constitutesfrom about 40 wt. % to about 95 wt. % of the core.
 7. The implantabledevice of claim 1, wherein the device is capable of releasing themacromolecular drug compound for a time period of about 5 days or more.8. The implantable device of claim 1, wherein after a time period of 15days, the device exhibits a cumulative release ratio of themacromolecular drug compound of from about 20% to about 70%.
 9. Theimplantable device of claim 1, wherein after a time period of 30 days,the device exhibits a cumulative release ratio of the macromoleculardrug compound of from about 40% to about 85%.
 10. The implantable deviceof claim 1, wherein vinyl acetate constitutes from about 20 wt. % toabout 55 wt. % of the first ethylene vinyl acetate copolymer, the secondethylene vinyl acetate copolymer, or both.
 11. The implantable device ofclaim 1, wherein the first ethylene vinyl acetate copolymer, the secondethylene vinyl acetate copolymer, or both has a melt flow index of fromabout 10 to about 80 grams per 10 minutes as determined in accordancewith ASTM D1238-13 at a temperature of 190° C. and a load of 2.16kilograms.
 12. The implantable device of claim 1, wherein the corepolymer matrix is formed entirely from hydrophobic polymers.
 13. Theimplantable device of claim 1, wherein the macromolecular drug compoundis a protein, peptide, enzyme, antibody, interferon, interleukin, bloodfactor, vaccine, nucleotide, lipid, or a combination thereof.
 14. Theimplantable device of claim 1, wherein the membrane layer is free of themacromolecular drug compound.
 15. The implantable device of claim 1,wherein the macromolecular drug compound constitutes from about 1 wt. %to about 40 wt. % of the membrane layer.
 16. The implantable device ofclaim 15, wherein the ratio of the concentration of the macromoleculardrug compound in the core to the concentration of the macromoleculardrug compound in the membrane layer is about 1.5 or more.
 17. Theimplantable device of claim 1, wherein the ratio of the melt flow indexof the first ethylene vinyl acetate copolymer to the melt flow index ofthe second ethylene vinyl acetate copolymer is from about 1 to about 20,as determined in accordance with ASTM D1238-13 at a temperature of 190°C. and a load of 2.16 kilograms.
 18. The implantable device of claim 1,wherein the hydrophilic compound is a hydrophilic polymer.
 19. Theimplantable device of claim 18, wherein the hydrophilic compoundconstitutes from about 1 wt. % to about 50 wt. % of the membrane polymermatrix and the second vinyl acetate copolymer constitutes from about 70wt. % to about 99 wt. % of the membrane polymer matrix.
 20. Theimplantable device of claim 18, wherein the hydrophilic compoundincludes a sodium, potassium or calcium alginate,carboxymethylcellulose, agar, gelatin, polyvinyl alcohol, polyalkyleneglycol, collagen, pectin, chitin, chitosan, poly-1-caprolactone,polyvinylpyrrolidone, poly(vinylpyrrolidone-co-vinyl acetate),polysaccharide, hydrophilic polyurethane, polyhydroxyacrylate, dextran,xanthan, hydroxypropyl cellulose, methylcellulose, protein, ethylenevinyl alcohol copolymer, water-soluble polysilane, water-solublesilicone, water-soluble polyurethane, a glycerin, a sugar, a salt, apeptide, or a combination thereof.
 21. The implantable device of claim1, wherein the core, membrane layer, or both contain a radiocontrastagent.
 22. The implantable device of claim 1, wherein the core definesan outer circumferential surface about which the membrane layer iscircumferentially disposed.
 23. The implantable device of claim 1,wherein the core defines an upper outer surface and a lower outersurface, the membrane layer being disposed adjacent to the upper outersurface.
 24. The implantable device of claim 23, further comprising asecond membrane layer positioned adjacent to the lower outer surface.25. The implantable device of claim 24, wherein the second membranelayer comprises a second membrane polymer matrix within which amacromolecular drug compound is optionally dispersed, wherein the secondmembrane polymer matrix contains a hydrophobic polymer in combinationwith a hydrophilic compound, wherein the weight ratio of the hydrophobicpolymer to the hydrophilic compound within the second membrane polymermatrix ranges from about 0.25 to about
 200. 26. The implantable deviceof claim 24, wherein the second membrane layer is free of the drugcompound.
 27. The implantable device of claim 1, wherein the core,membrane layer, or both are formed from a hot melt extrusion process.28. A method for prohibiting and/or treating a condition, disease,and/or cosmetic state of a patient, the method comprising subcutaneouslyimplanting the device of claim 1 in the patient.
 29. The implantabledevice of claim 1, wherein the drug compound has a molecular weight ofabout 1 kDa or more.
 30. The implantable device of claim 1, wherein thedrug compound has a molecular weight of from about 5 kDa to about 250kDa.
 31. The implantable device of claim 1, wherein the drug compoundcomprises a protein, an enzyme, or an antibody.
 32. The implantabledevice of claim 1, wherein the drug compound comprises a monoclonalantibody.